Pregnancy outcome following prenatal diagnosis of chromosomal anomaly: a record linkage study of 26,261 pregnancies

Previous studies have demonstrated the influence of changes in the age at which women give birth, and of developments in prenatal screening and diagnosis on the number of pregnancies diagnosed and terminated with chromosomal anomalies. However, we are unaware of any population studies examining pregnancy terminations after diagnosis of chromosomal anomalies that has included all aneuploidies and the influence of maternal factors. The aims of this study were to examine the association between results of prenatal tests and pregnancy termination, and the proportion of foetuses with and without chromosomal anomalies referred for invasive diagnostic tests over time. Diagnostic information of 26,261 prenatal invasive tests from all genetic service laboratories in Scotland from 2000 to 2011 was linked to Scottish Morbidity Records to obtain details on pregnancy outcome. Binary logistic regression was carried out to test the associations of year and type of diagnosis with pregnancy termination, while controlling for maternal age, neighbourhood deprivation and parity. There were 24,155 (92.0%) with no chromosomal anomalies, 1,483 (5.6%) aneuploidy diagnoses, and 623 (2.4%) diagnoses of anomaly that was not aneuploidy (including translocations and single chromosome deletions). In comparison with negative test results, pregnancies diagnosed with trisomy were most likely to be terminated (adjusted OR 437.40, 95% CI 348.19–549.46) followed by other aneuploid anomalies (adjusted OR 95.94, 95% CI 69.21–133.01). During the study period, fewer pregnancies that were diagnosed with aneuploidy were terminated, including trisomy diagnoses (adjusted OR 0.44, 95% CI 0.26–0.73). Older women were less likely to terminate (OR 0.35, 95% CI 0.28, 0.42), and parity was also an independent predictor of termination. In keeping with previous findings, while the number of invasive diagnostic tests declined, the proportion of abnormal results increased from 6.09% to 10.88%. Systematic advances in prenatal screening have improved detection rates for aneuploidy. This has been accompanied by a reduction in the rate of termination for aneuploidy. This may reflect societal changes with acceptance of greater diversity, but this is speculation, and further research would be needed to test this

Genetic testing of XY newborns with a suspected disorder of sex development

Purpose of review: The current review focuses on the neonatal presentation of disorders of sex development, summarize the current approach to the evaluation of newborns and describes recent advances in understanding of underlying genetic aetiology of these conditions. Recent findings: Several possible candidate genes as well as other adverse environmental factors have been described as contributing to several clinical subgroups of 46,XY DSDs. Moreover, registry-based studies showed that infants with suspected DSD may have extragenital anomalies and in 46,XY cases, being small for gestational age (SGA), cardiac and neurological malformations are the commonest concomitant conditions. Summary: Considering that children and adults with DSD may be at risk of several comorbidities a clear aetiological diagnosis will guide further management. To date, a firm diagnosis is not reached in over half of the cases of 46,XY DSD. Whilst it is likely that improved diagnostic resources will bridge this gap in the future, the next challenge to the clinical community will be to show that such advances will result in an improvement in clinical care

Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.</p

Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.</p

Cardiac disorders and structural brain abnormalities are commonly associated with hypospadias in children with neurodevelopmental disorders

Ther objective of our study was to use an established cohort of boys to investigate common patterns of malformations in those with hypospadias. We performed a retrospective review of the phenotype of participants in the Deciphering Developmental Disorders Study with neurodevelopmental delay and an 'Abnormality of the genital system'. This group was divided into two subgroups: those with hypospadias and without hypospadias. Associated phenotypes of the two subgroups were compared and analysed. Of the 166 Deciphering Developmental Disorders participants with hypospadias and neurodevelopmental delay, 47 (28%) had cardiovascular and 40 (24%) had structural brain abnormalities. The rate of cardiovascular abnormalities in those with neurodevelopmental delay and genital abnormalities other than hypospadias (N = 645) was lower at 19% (P = 0.001). In addition, structural brain malformations were higher at 24% in the hypospadias group versus 15% in the group without hypospadias (P = 0.002). The constellation of these features occured at a higher rate in the hypospadias group versus the no hypospadias group (P = 0.038). In summary, this is the first study to indicate that cardiovascular and brain abnormalities are frequently encountered in association with hypospadias in children with neurodevelopmental disorders. Not only do these associations provide insight into the underlying aetiology but also they highlight the multisystem involvement in conditions with hypospadias

The prevalence and nature of cardiac arrhythmias in horses following general anaesthesia and surgery

Background: The prevalence and nature of arrhythmias in horses following general anaesthesia and surgery is poorly documented. It has been proposed that horses undergoing emergency surgery for gastrointestinal disorders may be at particular risk of developing arrhythmias. Our primary objective was to determine the prevalence and nature of arrhythmias in horses following anaesthesia in a clinical setting and to establish if there was a difference in the prevalence of arrhythmias between horses with and without gastrointestinal disease undergoing surgery. Our secondary objective was to assess selected available risk factors for association with the development of arrhythmias following anaesthesia and surgery. Methods: Horses with evidence of gastrointestinal disease undergoing an exploratory laparotomy and horses with no evidence of gastrointestinal disease undergoing orthopaedic surgery between September 2009 and January 2011 were recruited prospectively. A telemetric electrocardiogram (ECG) was fitted to each horse following recovery from anaesthesia and left in place for 24 hours. Selected electrolytes were measured before, during and after surgery and data was extracted from clinical records for analysis. Recorded ECGs were analysed and the arrhythmias characterised. Multivariable logistic regression was used to identify risk factors associated with the development of arrhythmias. Results: Sixty-seven horses with gastrointestinal disease and 37 without gastrointestinal disease were recruited. Arrhythmias were very common during the post-operative period in both groups of horses. Supra-ventricular and bradyarrhythmias predominated in both groups. There were no significant differences in prevalence of any type of arrhythmias between the horses with or without gastrointestinal disease. Post-operative tachycardia and sodium derangements were associated with the development of any type of arrhythmia. Conclusions: This is the first study to report the prevalence of arrhythmias in horses during the post-operative period in a clinical setting. This study shows that arrhythmias are very common in horses following surgery. It showed no differences between those horses with or without gastrointestinal disease. Arrhythmias occurring in horses during the post-anaesthetic period require further investigation

Core elements of exemplary academic integrity policy in Australian higher education

This paper reports on one important aspect of the preliminary findings from the Australian Learning and Teaching Council (ALTC) project, Academic integrity standards: Aligning policy and practice in Australian universities. Our project aims to identify approaches to the complex issues of academic integrity, and then to build on these approaches to develop exemplars for adaptation across the higher education sector. Based on analysis of publicly available online academic integrity policies at each of the 39 Australian universities, we have identified five core elements of exemplary academic integrity policy. These have been grouped under the headings, Access, Approach, Responsibility, Detail and Support, with no element given priority over another. In this paper we compare the five core elements identified in our research with best practice guidelines recommended by the Higher Education Academy (HEA) in the UK. We conclude that an exemplar policy needs to provide an upfront, consistent message, reiterated throughout the entire policy, which indicates a systemic and sustained commitment to the values of academic integrity and the practices that ensure it. Whereas the HEA created two discrete resources, the key aim and challenge of this project will be to develop exemplars that demonstrate a strong alignment between policy and practice

Neonatal features of the Prader-Willi syndrome; the case for making the diagnosis during the first week of life

Early diagnosis is of proven benefit in Prader-Willi syndrome (PWS). We therefore examined key perinatal features to aid early recognition. Data were collected from case records of subjects attending a multi-disciplinary clinic and from a retrospective birth questionnaire. Ninety patients (54 male: 36 female) were seen between 1991-2015, most with paternal deletion (n=56) or maternal isodisomy (n=26). Features included cryptorchidism in 94% males, preterm birth (26%), birthweight &lt;2500g (24%), polyhydramnios (23%), breech presentation (23%) and need for nasogastric feeding (83%). Reduced fetal movements (FM) occurred in 82.5% patients compared with 4% healthy siblings. Of 35 children born since 1999, 23 were diagnosed clinically within 28 days while diagnosis in 12 was &gt; 28 days: 1-12 months in 7; and 3.75-10.5 years in 5. Typical PWS features in these 12 infants included hypotonia (100%), feeding difficulties (75%), cryptorchidism (83% males) and reduced FM (66%). Causes other than PWS including neuromuscular disease were considered in nine patients. Neonatal hypotonia, reduced FM, feeding difficulties and cryptorchidism should immediately suggest PWS, yet late diagnosis continues in some cases. Awareness of the typical features of PWS in newborn units is required to allow prompt detection even in the presence of confounding factors such as prematurity

Clinical and Genetic Evaluation of People with or at Risk of Hereditary ATTR Amyloidosis: An Expert Opinion and Consensus on Best Practice in Ireland and the UK

Hereditary transthyretin-mediated amyloidosis (hATTR) is challenging to diagnose early owing to the heterogeneity of clinical presentation, which differs according to the TTR gene variant and its penetrance in each individual. The TTR variants seen most frequently in the UK and Ireland (T80A, V142I and V50M) differ to those commonly occurring in other geographic locations and warrant a specific consideration for diagnosis and genetic testing. In addition, recent availability of treatment for this condition has reinforced the need for a more consistent approach to the management of patients, including access to specialist services, genetic testing and counselling, and clinical investigation for families living in the UK and Ireland. A multidisciplinary panel of experts from the UK and Ireland was convened to identify the current challenges, provide recommendations, and develop a consensus for the diagnosis and screening of people with, or at risk of, hATTR. Over a series of meetings, experts shared their current practices and drafted, refined and approved a consensus statement. This consensus statement provides recommendations for three different groups: (1) people with symptoms raising a possibility of hATTR amyloidosis; (2) people with biopsy-confirmed hATTR amyloidosis; and (3) people without symptoms who may have hATTR amyloidosis (i.e. relatives of people with identified TTR variants). For each group, recommendations are made for the required steps for the diagnosis and follow-up of symptomatic patients, and for guidance on the specialist support for counselling and pre-symptomatic genetic testing of at-risk individuals. This guidance is intended to be practical and based on available evidence. The aim is for regional amyloid specialist centres to provide timely diagnosis, clinical screening, and treatment for individuals and their families with hATTR amyloidosis